Sodium-glucose Co-transporter 2 Inhibitors for the Treatment of Type 2 Diabetes: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines

Shane Amanda; Robyn Butcher

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Cover of Sodium-glucose Co-transporter 2 Inhibitors for the Treatment of Type 2 Diabetes: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines

Sodium-glucose Co-transporter 2 Inhibitors for the Treatment of Type 2 Diabetes: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines

CADTH Rapid Response Report: Summary with Critical Appraisal

Shane Amanda and Robyn Butcher.

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Jun 14.

Abbreviations

AF: Atrial fibrillation
CVD: Cardiovascular disease
DBP: Diastolic blood pressure
DPP-4: Dipeptidyl peptidate IV
FBG: Fasting blood glucose
GLP-1: Glucagon-Like Peptide-1 Receptor agonist
HbA1c: Glycosylated hemoglobin
HF: Heart failure
HTA: Health Technology Assessment
MACE: Major adverse cardiovascular events
MI: Myocardial infarction
NMA: Network meta-analysis
RCT: Randomized controlled trial
SBP: Systolic blood pressure
SGLT2: Sodium-glucose co-transporter 2 inhibitor
SIGN: Scottish Intercollegiate Guidelines Network
SR: Systematic review
T2DM: Type 2 diabetes mellitus
TIA: Transient ischemic attack
UTI: Urinary tract infection

Context and Policy Issues

Type 2 diabetes mellitus (T2DM) is a chronic disease resulting from insufficient insulin production or inadequate cellular sensitivity to insulin.¹ It is associated with substantial disease burden both internationally and in Canada. In 2017, 7.3% of Canadians reported being diagnosed with diabetes², the majority of which (approximately 90%) were classified as T2DM.³ T2DM results in high blood glucose and is associated with increased risk of various medical conditions or complications including cardiovascular disease, blindness, renal disease, non-traumatic amputation, and death.⁴ The healthcare and other societal costs associated with diabetes are substantial.⁵

Management strategies are multifaceted, and can include physical activity, nutrition therapy, and pharmacological management.⁴ Typically, treatment for type 2 diabetes focuses on diet and exercise, followed by metformin. If insufficient, second-line treatments are considered.¹ Several second-line treatments are available, with different mechanisms of action, including sulfonylureas, insulins, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 analogues and sodium-glucose co-transporter 2 inhibitors.¹ Sodium-glucose co-transporter 2 inhibitors increase the amount of glucose excreted through the urine, thereby reducing blood glucose levels.⁶ Four sodium-glucose co-transporter 2 inhibitors are currently licensed for use in Canada: canagliflozin (INVOKANA©) 100 mg and 300 mg, empagliflozin (JARDIANCE©) 10 mg and 25 mg), dapagliflozin (FORXIGA©) 5 mg and 10 mg, and ertugliflozin (STEGLATRO©) 5 mg and 15 mg.⁷ With the introduction of this new class of glucose lowering drugs as second- or third-line therapy, institutional coverage decisions are required.

This report aims to summarize the comparative clinical effectiveness and comparative cost-effectiveness of sodium-glucose co-transporter 2 inhibitors for the treatment of adults with type 2 diabetes, as well as relevant evidence-based guidelines for the pharmacologic management of diabetes.

Research Questions

What is the comparative clinical effectiveness of sodium-glucose co-transporter 2 inhibitors for the treatment of adults with type 2 diabetes?
What is the comparative cost-effectiveness of sodium-glucose co-transporter 2 inhibitors for the treatment of adults with type 2 diabetes?
What are the evidence-based guidelines regarding the use of sodium-glucose co-transporter 2 inhibitors for the treatment of adults with type 2 diabetes?

Key Findings

Eleven systematic reviews with network meta-analyses of moderate quality were identified that addressed the comparative clinical effectiveness of sodium-glucose co-transporter 2 inhibitors across 21 outcomes. There were no significant differences in clinical effectiveness between the different sodium-glucose co-transporter 2 inhibitors for the majority of outcomes. When differences were observed, canagliflozin was more effective than other drugs in most cases.

No evidence regarding the comparative cost-effectiveness of sodium-glucose co-transporter 2 inhibitors was identified.

Four guidelines were identified; three of high quality and one of lower quality. Diabetes Canada recommends considering sodium-glucose co-transporter 2 inhibitors as add-on therapy in patients without cardiovascular disease (Grade A, Level 1A), and to temporarily withhold sodium-glucose co-transporter 2 inhibitors during reduced oral intake/dehydration, or before major surgery or acute infections (Grade D, consensus). The American College of Physicians recommends considering a sodium-glucose co-transporter 2 inhibitor as an option when adding a second oral therapy to metformin (weak recommendation; moderate-quality evidence). The Scottish Intercollegiate Guidelines Network recommends that sodium-glucose co-transporter 2 inhibitors are considered as add-on therapy to metformin (strong recommendation) and to consider empagliflozin and canagliflozin in patients with cardiovascular disease (strong recommendation). The fourth, lower quality guideline produced jointly by the American Diabetes Association and the European Association for the Study of Diabetes recommends the use of sodium-glucose co-transporter 2 inhibitors in patients with cardiovascular disease, heart failure or chronic kidney disease (strength of evidence or recommendations not provided).

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including Ovid Medline, the Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. The search strategy was comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were sodium-glucose co-transporter 2 inhibitors and type 2 diabetes. Search filters were applied to limit retrieval to health technology assessments (HTA), systematic reviews (SR), meta-analyses, or network meta-analyses, guidelines and economic studies. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2014 and May 15, 2019.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1

Selection Criteria.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to January 1, 2014. Guidelines with unclear methodology were also excluded.

Critical Appraisal of Individual Studies

The included SRs were critically appraised by one reviewer using Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR II)⁸ and guidelines were assessed with the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument.⁹ Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 440 citations were identified in the literature search. Following screening of titles and abstracts, 297 citations were excluded and 143 potentially relevant reports from the electronic search were retrieved for full-text review. Twenty potentially relevant publications were retrieved from the grey literature search for full text review. Of these potentially relevant articles, 148 publications were excluded for various reasons, and 15 publications met the inclusion criteria and were included in this report. These comprised 11 SRs for research question 1, no included studies for research question 2, and four evidence-based guidelines for research question 3.

Appendix 1 presents the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)¹⁰ flowchart of the study selection.

Summary of Study Characteristics

Additional details regarding the characteristics of included publications are provided in Appendix 2.

Study Design

The 11 SRs were published between 2016 to 2019 (three in each of 2016¹¹)¹²^,¹³, 2017¹⁴^–¹⁶ and 2018¹⁷^–¹⁹; two in 2019²⁰^,²¹) (Table 4). Taken together, they included literature published between the inception of key databases and May 2018. All SRs restricted study type for primary literature to randomized controlled trials (RCT). There were no head-to-head RCTs comparing the effectiveness of SGLT2s included in any SRs. Therefore, comparative clinical effectiveness was assessed via network meta-analyses in all cases. There was substantial overlap in RCTs contained in the SRs (overlap between SRs is presented in Table 10). Four relevant evidence-based guidelines were identified. Two guidelines were published in 2018, by the American Diabetes Association (ADA)/the European Association for the Study of Diabetes(EASD)²² and Diabetes Canada.⁴ The American College of Physicians (ACP)²³ and the Scottish Intercollegiate Guideline Network (SIGN)²⁴ published their guidelines in 2017 (Table 5).

All four guidelines relied on well-documented SRs for evidence collection, selection and synthesis, and recommendations were generated by consensus via a “guideline development group”. The Diabetes Canada, ACP and SIGN guideline development processes included a quality of evidence and strength of recommendations determination. Details regarding the rating systems are available in Table 2. The ADA/EASD recommendation statements did not report on the quality of the evidence or the strength of recommendations, and recommendations are considered author opinions.

Table 2

Ratings for evidence and recommendations for included guidelines.

Country of Origin

Seven SRs were conducted in China¹⁵^,¹⁶^,¹⁹^,²¹^,¹¹^,¹²^,¹⁴. The remaining four were conducted in the United Kingdom¹³, the United States²⁰, Canada¹⁸, and India¹⁷.

The four guidelines apply to the United States (n = 2), Canada (n = 1) and the United Kingdom (n = 1).

Patient Population

The study population of the SRs was patients (i.e., any age)¹⁶^,¹⁷^,¹⁹^,²⁰ or adults with T2DM.¹¹^–¹⁵^,¹⁸^,²¹

The prevalence of comorbidities among study participants included in the SRs was inconsistently reported across reviews. Information about CVD was reported in six of 11 SRs.¹¹^,¹²^,¹⁵^,¹⁷^,¹⁹^,²⁰ Alfayez et al. (2019)²⁰ reported a range of 66 to 100% prevalence of CVD among participants at time of enrollment in the included RCTs, and Tang et al. (2016)¹¹ reported a range of 8 to 99%. The remaining four SRs reported the proportion of included studies that enrolled patients with both T2DM and CVD (5.9 to 7.9% of studies included in SRs had patients with CVD).

Four SRs reported information on the prevalence of chronic kidney disease (CKD) or renal impairment among study participants.¹²^,¹⁵^,¹⁷^,¹⁹ Between 5.3 to 10.5% of included RCTs had patients with CKD.

The target populations for the guidelines are patients with T2DM (ADA/EASD²², ACP²³ and SIGN²⁴) and Canadians living with diabetes (Diabetes Canada⁴). The intended users of the ADA/EASD²², ACP²³ and SIGN²⁴ guidelines are clinicians. The Diabetes Canada⁴ guidelines are intended for healthcare professionals involved in the management of persons with T2DM.

Interventions and Comparators

Six SRs focused on various doses of canagliflozin, empagliflozin and dapagliflozin as interventions.¹¹^–¹⁴^,¹⁷^,¹⁹, Three SRs included canagliflozin, empagliflozin, dapagliflozin and additional SGLT2 inhibitors (i.e., ertugliflozin, ipragliflozin, lusogliflozin and tofogliflozin)¹⁶^,¹⁸^,²¹. Two SRs included additional, non-SGLT2 inhibitor interventions: Alfayez et al., 2019²⁰ included empagliflozin and canagliflozin, and additional interventions Dipeptidyl peptidate IV (DPP-4) inhibitors and Glucagon-Like Peptide-1 receptor (GLP-1) agonists, and Tang et al, 2016¹¹ included canagliflozin, dapagliflozin and empagliflozin as monotherapy and in combination with other antidiabetic drugs.

Comparators were placebo or other glucose-lowering medications. There were no head-to-head RCTs included in any SRs. Comparative clinical effectiveness was assessed with network meta-analyses (NMA) in all cases. The ADA/EASM, Diabetes Canada and ACP guidelines were broad, and considered all pharmacological interventions for T2DM that were licensed in their respective countries. The SIGN guidelines focused on SGLT2 inhibitors.

Outcomes

A variety of outcomes were included in the SRs. These included: glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight (change in weight from baseline), all-cause mortality, major adverse cardiovascular events (MACE), cardiovascular death, heart failure (HF), systolic blood pressure (SBP), low density lipoprotein (LDL), triglycerides, nonfatal myocardial infarction (MI), nonfatal stroke,, unstable angina/angina hospitalization, transient ischemic attack, cancer, renal outcomes, fracture risk, hypoglycaemia, urinary tract infection (UTI), genital infections.

Summary of Critical Appraisal

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

Systematic reviews with network meta-analysis

All SRs clearly defined the PICO elements in the research question(s) and inclusion/exclusion criteria, described key characteristics of included studies, and applied appropriate statistical methods for the network meta-analyses. No SR provided the list of excluded studies with reasons for exclusion (Table 6).

Most SRs were conducted with duplicate study selection and data extraction¹¹^–¹⁶^,²⁰^,²¹, and all but one declared no conflicts of interest. Four of six authors of the Zaccardi et al., 2016 SR received some form of funding from industry, and there was no description of how conflicts were addressed.¹³ Four studies either did not assess publication bias¹³^,¹⁹^,²⁰ or found significant publication bias.¹⁷ The remaining seven SRs did not detect publication bias.¹¹^,¹²^,¹⁴^,¹⁵^,¹⁸^,¹⁹^,²¹

The most variability in terms of methodological quality involved the results of the risk of bias assessment and how (or whether) the authors addressed any identified biases in the analysis or interpretation of the results. There was also inconsistency in how authors described the impact of heterogeneity on MA results.

Zaccardi et al., 2015¹³ conducted an SR with NMA to assess the comparative clinical effectiveness of SGLT2 inhibitors on eight outcomes. This SR had some methodological issues associated with high or unclear risk of bias in 11 and 17% of dapagliflozin and empagliflozin trials (Table 6). The authors did not describe how or whether clinical heterogeneity impacted the findings, and four of six authors reported relevant industry funding without description of how the conflicts of interest were managed. No other authors of included SRs reported conflicts of interest.

Azharuddin et al.¹⁷, Donnan et al.¹⁸, and Li et al.¹⁶ assessed the risk of bias using the Cochrane risk of bias tool. The extent to which the risk of bias was assessed and considered in interpreting the results varied for the other seven SRs. These studies also reported the statistical heterogeneity from their meta-analyses and NMAs, and provided sufficient interpretation regarding the impact of that heterogeneity on the results.

Evidence-based guidelines

The recommendation statements for the four guidelines were specific and unambiguous, they were easily identifiable, they presented different options for treatment of T2DM, and potential resource implications of applying the recommendations were considered (Table 7).

The guidelines from Diabetes Canada⁴, ACP²³ and SIGN²⁴ were comparable in terms of their performance on the remaining AGREE II domains. The objectives and populations were clear, the views and preferences of the target population were sought during development, target users were clearly defined, stakeholder involvement was strong and there was evidence of editorial independence. The rigour of development was generally strong; however, the method for formulating recommendations was not clear for the SIGN guideline, and the ACP guideline was not externally reviewed. Only the ACP guideline reported a clear procedure for updating the guideline.

In terms of applicability, only the SIGN guideline described facilitators and barriers to implementation and presented monitoring criteria.

In contrast to the other three guidelines, the ADA/EASM guideline²² had no or unknown stakeholder involvement, did not clearly describe the strengths and limitations of the evidence, did not describe the method for formulating recommendations, risks and benefits were not considered and there was no explicit link between the evidence and the recommendation statements. Further, editorial independence was unclear.

Summary of Findings

Appendix 4 presents a table of the main study findings and authors’ conclusions.

Comparative clinical effectiveness of sodium-glucose co-transporter 2 inhibitors

The comparative clinical effectiveness of various SGLT2 inhibitors was assessed against 21 outcomes in 11 SRs. A summary of findings, including effect measures by outcome is found in Table 3.

Table 3

Summary of findings for systematic reviews by outcome.

HbA1c

The comparative clinical effectiveness of various SGLT2 inhibitors on HbA1c was assessed via one SR.¹³ Zaccardi et al., 2015 conducted a moderate quality SR with NMA to compare the effects of canagliflozin 300 mg and 100 mg, dapagliflozin 10 mg and 5 mg, and empagliflozin 50 mg and 25 mg on this outcome. Canagliflozin 300 mg was associated with a significant reduction in HbA1c from baseline compared to all doses of dapagliflozin and empagliflozin.¹³

Fasting blood glucose

The comparative clinical effectiveness of various SGLT2 inhibitors on FBG was assessed via one SR. Zaccardi et al., 2015¹³ conducted a moderate quality SR with NMA to compare the effects of canagliflozin 300 mg and 100 mg, dapagliflozin 10 mg and 5 mg, and empagliflozin 50 mg and 25 mg on this outcome. Canagliflozin 300 mg was associated with a significant reduction in FBG from baseline compared to dapagliflozin 10 mg, empagliflozin 10 mg, and empagliflozin 25 mg. Canagliflozin 100 mg was associated with a significant reduction in FBG compared to dapagliflozin 5 mg.¹³

Body weight

The comparative clinical effectiveness of various SGLT2 inhibitors on change in body weight from baseline was assessed via two SRs.¹³^,²¹ Wang et al., 2019 conducted a high-quality NMA to compare the effects of canagliflozin, dapagliflozin empagliflozin, ertugliflozin, ipragliflozin, lusogliflozin and tofogliflozin on change in body weight.²¹. Canagliflozin was associated with significant reduction in body weight compared to the other included SGLT2 inhibitors.

Zaccardi et al., 2015¹³ conducted a moderate quality SR with NMA to compare the effects of canagliflozin 300 mg and 100 mg, dapagliflozin 10 mg and 5 mg, and empagliflozin 50 mg and 25 mg on change in body weight. Canagliflozin 300 mg was associated with a significant decrease in body weight compared to dapagliflozin 5 mg. Dapagliflozin 5 mg was associated with a significant increase in body weight compared to empagliflozin 10 mg and empagliflozin 25 mg. However, there was significant inconsistency observed in this network analysis; therefore, the authors recommended caution when interpreting the results of the association between canagliflozin, empagliflozin and dapagliflozin on changes in body weight.

All-cause mortality and MACE

The comparative clinical effectiveness of various SGLT2 inhibitors on all-cause mortality and MACE was assessed via three SRs.¹¹^,¹⁹^,²⁰

Alfayez et al., 2019²⁰ found no significant difference in all-cause mortality or MACE between canagliflozin and empagliflozin. Zhuang et al., 2018¹⁹ and Tang et al., 2016¹¹ found no significant difference between canagliflozin, dapagliflozin and empagliflozin and all-cause mortality or MACE.

Cardiovascular death

The comparative clinical effectiveness of various SGLT2 inhibitors on cardiovascular death was assessed via one SR.²⁰. A network meta-analysis with important limitations (Table 6) was conducted to compare the effect of empagliflozin and canagliflozin, and there were no significant differences between empagliflozin and canagliflozin with respect to cardiovascular death.

Heart failure

The comparative clinical effectiveness of various SGLT2 inhibitors on heart failure was assessed via two SRs.¹¹^,²⁰ Tang et al., 2016 compared the effect of canagliflozin, dapagliflozin and empagliflozin on the risk of heart failure, and found no difference between any SGLT2 inhibitor treatments. Alfayez et al., 2019 compared the effect of canagliflozin and empagliflozin on the risk of heart failure, and found no difference between these treatments.

SBP

The comparative clinical effectiveness of various SGLT2 inhibitors on change in SBP from baseline was assessed via one SR. Zaccardi et al., 2015¹³ conducted a moderate quality SR with NMA to compare the effects of canagliflozin 300 mg and 100 mg, dapagliflozin 10 mg and 5 mg, and empagliflozin 50 mg and 25 mg on this outcome. Canagliflozin 300 mg was associated with a significant reduction in SBP compared to dapagliflozin 5 mg, dapagliflozin 10 mg and empagliflozin 10 mg.¹³

LDL

The comparative clinical effectiveness of various SGLT2 inhibitors on LDL was assessed via one SR.¹³ A high-quality NMA was conducted to compare the effects of canagliflozin 300 mg and 100 mg, dapagliflozin 10 mg and 5 mg, and empagliflozin 50 mg and 25 mg on this outcome. Canagliflozin 300 mg was associated with a significant increase in LDL compared to all doses of dapagliflozin and empagliflozin.¹³

Triglycerides

The comparative clinical effectiveness of various SGLT2 inhibitors on triglycerides was assessed via one SR. Zaccardi et al., 2015¹³ conducted a moderate quality SR with NMA to compare the effects of canagliflozin 300 mg and 100 mg, dapagliflozin 10 mg and 5 mg, and empagliflozin 50 mg and 25 mg on this outcome. Canagliflozin 300 mg and 100 mg were both associated with a significant reduction in triglycerides compared to empagliflozin 10 mg and empagliflozin 25 mg.¹³

Non-fatal myocardial infarction

The comparative clinical effectiveness of various SGLT2 inhibitors on non-fatal myocardial infarction was assessed via one SR.²⁰. A network meta-analysis with important limitations (Table 6) was conducted to compare the effects of empagliflozin and canagliflozin, there were no significant differences with respect to non-fatal myocardial infarction.

Non-fatal stroke

The comparative clinical effectiveness of various SGLT2 inhibitors on non-fatal stroke was assessed via one SR.²⁰. A network meta-analysis with important limitations (Table 6) was conducted to compare the effects of empagliflozin and canagliflozin, and there were no significant differences between empagliflozin and canagliflozin for non-fatal stroke.

Unstable angina/angina requiring hospitalization

The comparative clinical effectiveness of various SGLT2 inhibitors on unstable angina or angina requiring hospitalization was assessed via one SR.¹¹. A network meta-analysis with important limitations (Table 6) was conducted to compare the effects of canagliflozin, empagliflozin and dapagliflozin on this outcome. There were no significant differences between canagliflozin, empagliflozin or dapagliflozin with respect to angina. The authors conducted a mean rank analysis which calculated the probability of a treatment being most to least safe. For unstable angina/angina requiring hospitalization, a rank order (from best) was determined to be canagliflozin, dapagliflozin, empagliflozin, placebo, and other active treatments.

Atrial fibrillation

The comparative clinical effectiveness of various SGLT2 inhibitors on AF was assessed via one SR.¹¹. A network meta-analysis with important limitations (Table 6) was conducted to compare the effects of canagliflozin, empagliflozin and dapagliflozin on this outcome, and there were no significant differences with respect to AF. The authors conducted a mean rank analysis which calculated the probability of a treatment being most to least safe. For AF, a rank order (from best) was determined to be empagliflozin, canagliflozin, dapagliflozin, placebo, and other active treatments.

Transient ischemic attack

The comparative clinical effectiveness of various SGLT2 inhibitors on TIA was assessed via one SR.¹¹. A network meta-analysis with important limitations (Table 6) was conducted to compare the effects of canagliflozin, empagliflozin and dapagliflozin, and there were no significant differences. The authors conducted a mean rank analysis which calculated the probability of a treatment being most to least safe. For TIA, a rank order (from best) was determined to be dapagliflozin, empagliflozin, canagliflozin, other active treatments and placebo.

Cancer

The comparative clinical effectiveness of various SGLT2 inhibitors on risk of cancer was assessed via one SR.¹⁴. A network meta-analysis with important limitations (Table 6) was conducted to compare the effects of canagliflozin, empagliflozin and dapagliflozin, and there were no significant differences

Renal outcomes

The comparative clinical effectiveness of various SGLT2 inhibitors on risk of renal outcomes was assessed via one SR.¹⁵. A network meta-analysis was conducted to compare the effects of canagliflozin, empagliflozin and dapagliflozin and luseogliflozin, there were no significant differences.

Fracture risk

The comparative clinical effectiveness of various SGLT2 inhibitors on risk of genital infection was assessed via two SRs.¹²^,¹⁷ Both conducted NMAs to compare the effects of canagliflozin, empagliflozin, and dapagliflozin on the risk of fracture, and there were no significant differences.

Hypoglycaemia

The comparative clinical effectiveness of various SGLT2 inhibitors on the risk of hypoglycemia was assessed via one SR. Zaccardi et al., 2015¹³ conducted a moderate quality SR with NMA to compare the effects of canagliflozin 300 mg and 100 mg, dapagliflozin 10 mg and 5 mg, and empagliflozin 50 mg and 25 mg on this outcome. Canagliflozin 300 mg was associated with a significant reduction in the risk of hypoglycemia compared to empagliflozin 10 mg. Canagliflozin 100 mg was associated with a significant reduction in the risk of hypoglycemia compared to dapagliflozin 10 mg and empagliflozin 10 mg.¹³

Urinary tract infection

The comparative clinical effectiveness of various SGLT2 inhibitors on risk of urinary tract infection was assessed via three SRs.¹³^,¹⁶^,¹⁸ Donnan et al., 2018¹⁸ compared the effect of canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, leusogliflozin, remogliflozin, togogliflozin and ertugliflozin on the risk of urinary tract infection. High dose dapagliflozin (≥10 mg) was associated with significantly increased risk of urinary tract infection compared to high dose empagliflozin (≥25 mg), low dose empagliflozin (≤10 mg) and low dose ertugliflozin (≤10 mg). Zaccardi et al., 2015¹³ compared the effect of canagliflozin, dapagliflozin and empagliflozin on risk of urinary tract infection. Dapagliflozin 10 mg was associated with significantly increased risk of urinary tract infection compared to empagliflozin 25 mg. Li et al.,2017¹⁶ compared the effect of canagliflozin, empagliflozin, dapagliflozin, luseogliflozin and ipragliflozin on the risk of urinary tract infection. Empagliflozin was associated with significantly lower risk of urinary tract infection than dapagliflozin.

Genital infection

The comparative clinical effectiveness of various SGLT2 inhibitors on risk of genital infection was assessed via one SR.¹⁶. A network meta-analysis with important limitations (Table 6) was conducted to compare the effects of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, and luseogliflozin, and there were no significant differences

Comparative cost-effectiveness of sodium-glucose co-transporter 2 inhibitors

No relevant evidence regarding the comparative cost-effectiveness of SGLT2 inhibitors was identified; therefore, no summary can be provided.

Evidence-based guidelines regarding the use of sodium-glucose co-transporter 2 inhibitors

Among the four guidelines included in this report, one (the SIGN guideline) included a recommendation about specific SGLT2 inhibitors (i.e., empagliflozin and canagliflozin)²⁴. The remaining three guidelines made recommendations about SGLT2 inhibitors as a class (Table 9).

SIGN²⁴ recommends that individuals with established cardiovascular disease consider the use of empagliflozin or canagliflozin (strong recommendation) as second-line therapy, or when metformin is not tolerated or is contraindicated. SIGN refers to the “proven cardiovascular benefit” (p. 23) of these two SGLT2 inhibitors.

The ADA/EASD²² recommends use of SGLT2 inhibitors among patients with atherosclerotic cardiovascular disease and heart failure, and patients with chronic kidney disease.

Diabetes Canada⁴ recommends that SGLT2 inhibitors be considered (along with dipeptidyl peptidate IV or glucagon-like peptide-1 receptor agonists) in adults with type 2 diabetes mellitus without cardiovascular disease, when glycemic targets are not being met with existing medication (Grade A, Level 1A).

The ACP recommends an SGLT2 inhibitor as an option for an add-on treatment to metformin when considering a second oral therapy (Weak recommendation, moderate-quality evidence).²³

Limitations

The clinical effectiveness of SGLT2 inhibitors against of six of 21 outcomes (HbA1c, fasting blood glucose, systolic blood pressure, low density lipoprotein, triglycerides and hypoglycemia) was assessed through one systematic review¹³ that had some important methodological limitations. These included high risk of bias in many included RCTs and reported conflicts of interest among the majority of authors. Confidence in the measures of association would be increased if additional systematic reviews found consistent results.

There were no head-to-head trials for SGLT2 inhibitors; therefore, the body of evidence presented in this report was indirect. Generating indirect evidence relies on the homogeneity assumption for meta-analysis, but also a similarity assumption (assumption that the effects for each comparison to the common intervention [e.g. usually placebo] are similar).²⁵ No systematic review specifically addressed the extent to which these assumptions were met or not met by the included RCTs within their studies.

Six of 11 systematic reviews reported the prevalence of patients with cardiovascular disease at baseline. However, no study included subgroup analysis on the clinical effectiveness of SGLT2 inhibitors among patients with versus without cardiovascular disease. Therefore, no evidence was identified to inform whether the effectiveness or safety of SGLT2 inhibitors is modified by the presence or absence of cardiovascular disease. There were no Canadian comparative cost-effectiveness studies identified in this review, therefore coverage decisions would have to rely on clinical effectiveness only, or non-Canadian cost-effectiveness evidence.

Conclusions and Implications for Decision or Policy Making

Eleven systematic reviews with network meta-analyses were included to inform the comparative clinical effectiveness of SGLT2 inhibitors, and four evidence-based guidelines were summarized to inform recommendations for the use of SGLT2 inhibitors. No publications were identified to address the comparative cost-effectiveness of SGLT2 in the Canadian setting.

The evidence suggests that the three SGLT2 inhibitors of interest (i.e. canagliflozin, empagliflozin and dapagliflozin) have comparative clinical effectiveness (i.e. no statistically significant differences in association) against several outcomes: all-cause mortality, cardiovascular death, major adverse cardiovascular events, heart failure, angina, atrial fibrillation, non-fatal myocardial infarction, non-fatal stroke, transient ischemic attack, cancer, acute renal impairment and fracture risk.

When significant differences were observed, canagliflozin was more effective than other SGLT2 inhibitors in most cases. Canagliflozin was associated with decreased HbA1c, fasting blood glucose, systolic blood pressure, triglycerides and weight, compared to other SLGT2 inhibitors. However, canagliflozin was also associated with increased hypotension and high density lipoprotein.

Dapagliflozin was associated with decreased fasting blood glucose and decreased body weight from baseline, compared with empagliflozin. However, there was evidence of increased urinary tract infections compared to empagliflozin.

Empagliflozin was associated with decreased risk of composite renal events and urinary tract infection compared to dapagliflozin.

One organization made clinical practice recommendations about the differential use of treatments within the SGLT2 inhibitor drug class. SIGN²⁴ recommends that empagliflozin and canagliflozin be considered as second-line therapies, or when metformin is not tolerated or is contraindicated among patients with cardiovascular disease (strong recommendation). There was some inconsistency in SGLT2 drug class recommendations across the remaining reviewed guidelines. The ADA/EASD²² recommends use of SGLT2 inhibitors for patients with atherosclerotic cardiovascular disease and heart failure, and patients with chronic kidney disease (grade of recommendation not provided). Conversely, Diabetes Canada⁴ recommends SGLT2 inhibitors in adults without cardiovascular disease (Grade A, Level 1A). The ACP²³ does not make a statement about use of SGLT2 inhibitors among patients with comorbidities (e.g., CVD, CKD), but recommends the class as an option for add-on treatment to metformin when considering a second oral therapy (Weak recommendation; moderate-quality evidence).

A large body of moderate to high quality evidence from systematic reviews and network meta-analyses exists to inform the comparative clinical effectiveness of SGLT2 inhibitors. Canagliflozin was associated with the most clinical benefits, and fewest risks compared to other SGLT2 inhibitors. Further research regarding Canadian comparative cost-effectiveness is needed to complement the clinical effectiveness data, in order to inform coverage decisions for the SGLT2 inhibitor drug class.

References

1.: Second-line therapy for type 2 diabetes. (CADTH In brief: a summary of the therapeutic review project). Ottawa (ON): CADTH; 2017: https://www.cadth.ca/sites/default/files/pdf/second_line_therapy_for_type_2_diabetes_in_brief_e.pdf. Accessed 2019 June 14.
2.: Statistics Canada. Health fact sheets: diabetes. 2017; https://www150.statcan.gc.ca/n1/pub/82-625-x/2018001/article/54982-eng.htm. Accessed 2019 Jun 14.
3.: Government of Canada. Diabetes in Canada. 2017; https://www.canada.ca/en/publichealth/services/publications/diseases-conditions/diabetes-canada-highlights-chronic-disease-surveillancesystem.html#box1. Accessed 2019 June 14.
4.: Diabetes Canada guidelines. Toronto (ON): Diabetes Canada; 2018: http://guidelines.diabetes.ca/docs/CPG-2018-full-EN.pdf. Accessed 2019 June 14.
5.: Bilandzic A, Rosella L. The cost of diabetes in Canada over 10 years: applying attributable health care costs to a diabetes incidence prediction model. Health Promot Chronic Dis Prev Can. 2017;37(2):49–53. [PMC free article: PMC5607525] [PubMed: 28273040]
6.: DeSantis Anthony. Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus. In: Nathan DM, Mulder JE, eds. UpToDate. Waltham (MA): UpToDate; 2018: www.uptodate.com. Accessed 2019 June 14.
7.: Health Canada. Flozin. 2019; https://hpr-rps.hres.ca/query.php?drugquery=flozin. Accessed 2019 June 14.
8.: Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. http://www.bmj.com/content/bmj/358/bmj.j4008.full.pdf. Accessed 2019 June 14. [PMC free article: PMC5833365] [PubMed: 28935701]
9.: Agree Next Steps Consortium. The AGREE II Instrument. [Hamilton, ON]: AGREE Enterprise; 2017: https://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdf. Accessed 2019 June 14.
10.: Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–e34. [PubMed: 19631507]
11.: Tang H, Fang Z, Wang T, Cui W, Zhai S, Song Y. Meta-analysis of effects of sodium-glucose co-transporter 2 inhibitors on cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes mellitus. Am J Cardiol. 2016;118(11):1774–1780. [PubMed: 27666177]
12.: Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016;18(12):1199–1206. [PubMed: 27407013]
13.: Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18(8):783–794. [PubMed: 27059700]
14.: Tang H, Dai Q, Shi W, Zhai S, Song Y, Han J. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia. 2017;60(10):1862–1872. [PubMed: 28725912]
15.: Tang H, Li D, Zhang J, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(8):1106–1115. [PubMed: 28240446]
16.: Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(3):348–355. [PubMed: 27862830]
17.: Azharuddin M, Adil M, Ghosh P, Sharma M. Sodium-glucose co-transporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: a systematic literature review and Bayesian network meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2018;146:180–190. [PubMed: 30389620]
18.: Donnan JR, Grandy CA, Chibrikov E, et al. Dose response of sodium glucose cotransporter-2 inhibitors in relation to urinary tract infections: a systematic review and network meta-analysis of randomized controlled trials. CMAJ Open. 2018;6(4):E594–E602. [PMC free article: PMC6287977] [PubMed: 30530719]
19.: Zhuang XD, He X, Yang DY, et al. Comparative cardiovascular outcomes in the era of novel anti-diabetic agents: a comprehensive network meta-analysis of 166,371 participants from 170 randomized controlled trials. Cardiovasc Diabetol. 2018;17(1):79. [PMC free article: PMC5989345] [PubMed: 29871636]
20.: Alfayez OM, Al Yami MS, Alshibani M, et al. Network meta-analysis of nine large cardiovascular outcome trials of new antidiabetic drugs. Prim Care Diabetes. 2019;13(3):204–211. [PubMed: 30713085]
21.: Wang H, Yang J, Chen X, Qiu F, Li J. Effects of sodium-glucose co-transporter 2 inhibitor monotherapy on weight changes in patients with type 2 diabetes mellitus: a Bayesian network meta-analysis. Clin Ther. 2019;41(2):322–334.e311. [PubMed: 30711143]
22.: Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in Type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669–2701. [PMC free article: PMC6245208] [PubMed: 30291106]
23.: Qaseem A, Barry MJ, Humphrey LL, Forciea MA, Clinical Guidelines Committee of the American College of P. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279–290. [PubMed: 28055075]
24.: Pharmacological management of glycaemic control in people with type 2 diabetes. (SIGN publication no.154). Edinburgh (GB): Scottish Intercollegiate Guidelines Network (SIGN): https://www.sign.ac.uk/assets/sign154.pdf. Accessed 2019 June 14.
25.: Song F, Loke YK, Walsh T, Glenny AM, Eastwood AJ, Altman DG. Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. BMJ. 2009;338:b1147. [PMC free article: PMC2665205] [PubMed: 19346285]

Appendix 1. Selection of Included Studies

Appendix 2. Characteristics of Included Publications

Table 4Characteristics of Included Systematic Reviews and Meta-Analyses

First Author, Publication Year, Country

Study Designs and Numbers of Primary Studies Included

Population Characteristics

Intervention and Comparator(s)

Clinical Outcomes, Length of Follow-Up

Alfayez, 2019,

United States and Saudi Arabia

9 randomized controlled trials including

2 trials for SGLT2 (EMP-REG and CANVAS)

Literature search between 2008 and December 2017

Patients with T2DM

All included RCTs had participants with CVD at enrolments (prevalence at enrolment range: 66 to 100%)

Interventions of Interest for this Report: SGLT2 (EMPA, CANA)

Additional Interventions: DPP-4 inhibitors, GLP-1 agonists

Comparator: PLA

Primary: MACE, death from CV causes, nonfatal MI, nonfatal stroke, and death from any cause

Secondary: hospitalization for HF and unstable angina

Follow up for two SGLT2 trials: median 3.1 and 2.4 years

Wang, 2019,

China

32 RCTs across 29 publications

Literature search from inception to January 2018

Patients >18 years with T2DM

Prevalence of comorbidities among study participants not summarized

Interventions of Interest for this Report: CANA, DAPA, EMPA, ERTU, IPRA, LUSO and TOFO)

Additional Interventions: none

Comparators:. PLA or other oral glucose-lowering medication

Change in weight from baseline (continuous) and proportion with ≥5% weight reduction (categorical)

Follow-up ranged from 12 and 76 weeks

Azharuddin, 2018,

India

40 RCTs

Literature search from inception to May 2018

Patients with T2DM

4/40 RCTs included patients with pre-existing CKD. Prevalence not reported.

3/40 RCTs included patients with pre-existing CVD. Prevalence not reported.

Interventions of Interest for this Report: CANA, DAPA and EMPA)

Additional Interventions: none

Comparators: PLA or other antidiabetic treatments

Fracture events

Follow-up ranged from 24 to 160 weeks

Donnan, 2018,

Canada

108 RCTs across 105 publications

93 trials for SGLT2

Literature search from inception to May 2018

Patients ≥18 years with T2DM

Prevalence of comorbidities among study participants not summarized

Interventions of Interest for this Report: DAPA, EMPA, CANA, IPRA, LUSEO, REMO, TOGO, ERTU)

Additional Interventions: none

Comparators: PLA, no treatment or active antidiabetic control (except sulphonylureas)

UTI

Follow-up ranged from 1 to 208 weeks

Zhuang, 2018,

China

170 RCTs

39 trials for SGLT2

Patients with T2DM

10/170 RCTs include patients with high cardiovascular risk (prevalence among participants not reported)

9/170 RCTs include patients with renal impairment (prevalence among participants not reported)

Interventions of Interest for this Report: CANA, DAPA, EMPA

Other Interventions: none

Comparators: CANA, DAPA, EMPA, other positive comparator drugs or PLA

MACE, non-fatal stroke, unstable angina or hospitalization for unstable angina, all-cause mortality

Follow-up ranged from 24 to 208 weeks

Li, 2017,

China

52 RCTs

Patients with T2DM

Prevalence of comorbidities among study participants not summarized

Interventions of Interest for this Report: CANA, DAPA, EMPA, LUSEO, IPRA

Other Interventions: none

Comparators: PLA or other oral antidiabetic drugs

UTI and genital infections

Follow-up ranged from 24 to 160 weeks

Tang, 2017,

China and United States

46 RCTs

Adults with T2DM

Prevalence of comorbidities among study participants not summarized

Interventions of Interest for this Report: CANA, DAPA, EMPA

Other Interventions: none

Comparators:. PLA or other active glucose-lowering treatment

Primary: risk of overall cancer

Secondary: risk of pre-specified cancer types including skin, breast, respiratory, gastrointestinal, bladder, prostate and renal

Follow-up ranged from 24-160 weeks

Tang, 2017,

China and United States

59 datasets across 58 RCTs

Adults with T2DM

Prevalence of CVD among study participants reported in 4/59 RCTs

Prevalence of CKD among study participants reported in 5/59 RCTs

Interventions of Interest for this Report: CANA, DAPA, EMPA or LUSEO

Other Interventions: none

Comparators: PLA or other active antidiabetic treatments

Renal-related adverse outcomes (increased creatinine or BUN levels, decreased eGFR, renal impairment or renal failure).

Follow-up ranged from 12 to 160 weeks

Tang, 2016,

China and United States

37 RCTs

Patients ≥ 18 years with T2DM

Prevalence of CVD among study participants reported in 8/37 RCTs (range: 8 to 99%)

Interventions of Interest for this Report: CANA, DAPA or EMPA monotherapy

Other interventions: CANA, DAPA or EMPA in combination with other antidiabetic drugs

Comparators: PLA, other SGLT2, or other active treatment

Primary: all-cause mortality, MACE (including death from CV causes, nonfatal MI or non-fatal stroke).

Secondary: HF or HF requiring hospitalization, unstable angina or unstable angina requiring hospitalization, AF and TIA.

Follow-up ranged from 24 to 260 weeks

Tang, 2016,

China and United States

38 RCTs

Adults with T2DM

Prevalence of CKD among study participants reported in 4/38 RCTs

Prevalence of CKD among study participants reported in 3/38 RCTs

Interventions of Interest for this Report: CANA, DAPA, EMPA

Other Interventions: none

Comparators: PLA or other active antidiabetic treatments

Any time of fracture event

Follow-up ranged from 24 to 260 weeks

Zaccardi, 2015,

United Kingdom

38 RCTs

Adults with T2DM

Prevalence of comorbidities among study participants not summarized

Interventions of Interest for this Report: CANA, DAPA, EMPA

Other Interventions: none

Comparators: PLA or other glucose-lowering drugs

Primary: HbA1c, FPG, body weight

Secondary: SBP, DBP, total cholesterol, LDL, HDL, triglycerides

Safety outcomes: all hypoglycemic events, UTI, genital infection, diabetic ketoacidosis, bone fractures.

Follow-up ranged from 24 to 208 weeks.

: AF = atrial fibrillation; BMI = body mass index; BUN = blood urea nitrogen; CANA = canagliflozin; CKD = chronic kidney disease; CVD = cardiovascular disease; CANVAS = canagliflozin cardiovascular assessment study; DAPA = dapagliflozin; DPP-4 inhibitors = Dipeptidyl peptidate IV inhibitor; eGFR = estimated glomerular filtration rate; EMPA = empagliflozin; EMPA-REG = empagliflozin cardiovascular outcomes and mortality in type 2 diabetes trial; ERTU = ertugliflozin; FPG = fasting plasma glucose; GLP-1RA = Glucagon-Like Peptide-1 Receptor agonist; GMI = genital mycotic infection; HbA1c = glycated hemoglobin; HDL = high density lipoprotein; HF = heart failure; IPRA = ipragliflozin; LDL = low density lipoprotein; LUSEO = luseogliflozin; MACE = major adverse cardiovascular events; MET = metformin; MI = myocardial infarction; NSHE = non-severe hypoglycemic event; PLA = placebo; REMO = remogliflozin; SBP = systolic blood pressure; SGLT-2 = Sodium-glucose co-transporter 2 inhibitor; SHE = severe hypoglycemic event; T2DM = type 2 diabetes mellitus; TIA = transient ischemic attack; TOGO = togogliflozin; UTI = urinary tract infection.

Table 5Characteristics of Included Guidelines

Intended Users, Target Population	Intervention and Practice Considered^*	Major Outcomes Considered^*	Evidence Collection, Selection, and Synthesis	Evidence Quality Assessment	Recommendations Development and Evaluation	Guideline Validation
American Diabetes Association and the European Association for the Study of Diabetes, 2018²²
Intended Users: clinicians Target population: adults with T2DM	Effectiveness and safety of pharmacological or non-pharmacological interventions in adults with T2DM	ASCVD	Literature search of one database for SRs and MAs published in English between 1 January 2014 and 28 February 2018. Hand searching.	None	Recommendations are considered author opinions	Draft consensus recommendations peer reviewed
Diabetes Canada, 2018⁴
Intended Users: clinicians Target population: Canadians living with diabetes	Pharmacological glycemic management of newly diagnosed people with T2DM and treatment advancement in people with T2DM in whom glycemic targets not achieved with existing antihyperglycemic medication	HbA1c lowering, hypoglycemia, weight, effect on primary CVD outcomes	Systematic literature review	Evidence quality was assessed against a “levels of evidence” table (levels 1 [high] to 4 [low])	Recommendations developed by expert committee members after evaluating relevant literature; assigned grades from A (best) to D.	Draft recommendation statements peer reviewed
ACP 2017²³
Intended Users: all clinicians Target population: adults with T2DM	Metformin, thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and SGLT-2 inhibitors.	Intermediate outcomes: HbA1c, weight, SBP and HR. Long-term outcomes: All-cause mortality, cardiovascular mortality, retinopathy, nephropathy and neuropathy, genital mycotic infections Other: UTI, impaired renal function, genital mycotic infections, fracture and volume depletion	Systematic literature review	American College of Physicians’ Guideline Grading system	Recommendation statements developed through consideration of magnitude of benefits, harms, costs, resource issues, implementation considerations, patient and caregiver concerns and legal matters by the Clinical Guidelines Committee.	Evidence review peer reviewed, and posted publically for public comment
SIGN, 2017 ²⁴
Intended Users: healthcare professionals involved in the management of persons with T2DM Target population: adults with T2DM	SGLT2 inhibitor treatment	Mortality, CVD morbidity and mortality, microvascular morbidity, HbA1c, weight, hypoglycaemia and other AE	Systematic literature review	Levels of evidence (1 [high] to 4) and strength of recommendations	Recommendations were made by the Guideline Development Group in consideration of evidence obtained from systematic review.	Draft guideline posted online for comment.

*: interventions/outcomes relevant to SGLT2 treatment.
: ASCVD = atherosclerotic cardiovascular disease; MA = meta-analysis; GRADE = the Grading of Recommendations, Assessment, Development and Evaluation; SR = systematic review; T2DM = type 2 diabetes mellitus.

Appendix 3. Critical Appraisal of Included Publications

Table 6Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR II⁸

Strengths	Limitations
Alfayez, 2019²⁰
PICO elements included in research questions and inclusion/exclusion criteria Duplicate study selection and data extraction Characteristics of included studies provided Applied appropriate statistical methods for NMA Cochrane RoB results included No COI declared	No explicit explanation of restriction to RCTs Search strategy not provided List of excluded studies not provided Authors noted methodological heterogeneity across included studies as a limitation but did not address it statistically Statistical heterogeneity across meta-analysis results inconsistently reported and impact of heterogeneity not discussed Limited discussion regarding impact of RoB on meta-analysis results, and in general; however, all included studies determined to have low RoB across all Cochrane RoB instrument domains Publication bias not assessed Funding source of included studies not reported
Wang, 2019²¹
PICO elements included in inclusion/exclusion criteria Duplicate study selection and data extraction Characteristics of included studies provided Applied appropriate statistical methods for NMA Cochrane RoB results included No publication bias No COI declared	No explicit explanation of restriction to RCTs Search strategy not provided List of excluded studies not provided No discussion of how methodological or statistical heterogeneity impacted results Funding source of included studies not reported
Azharuddin, 2018¹⁷
PICO elements included in inclusion/exclusion criteria Search strategy provided Duplicate data extraction Characteristics of included studies provided Applied appropriate statistical methods for NMA Interpreted effect of heterogeneity on results Cochrane RoB results included No COI declared	No explicit explanation of restriction to RCTs Duplicate screening unknown List of excluded studies not provided Funding source of included studies not reported Publication bias found via Begg’s adjusted rank correlation, but not with Egger’s linear regression test
Donnan, 2018¹⁸
PICO elements included in research question and inclusion/exclusion criteria Search strategy provided Characteristics of included studies provided Applied appropriate statistical methods for NMA Interpreted effect of heterogeneity on results Cochrane RoB results included No publication bias No COI declared	Duplicate screening only for citations rejected by first reviewer Data extraction by one reviewer with verification by a second List of excluded studies not provided Funding source of included studies not reported
Zhuang, 2018¹⁹
PICO elements included in research question and inclusion/exclusion criteria Search strategy provided Duplicate screening Characteristics of included studies provided Applied appropriate statistical methods for NMA No COI declared	No explicit explanation of restriction to RCTs Unclear methods for data extraction List of excluded studies not provided No discussion of how methodological or statistical heterogeneity impacted results Publication bias not assessed Funding source of included studies not reported
Li, 2017¹⁶
PICO elements included in research question and inclusion/exclusion criteria Search strategy provided Duplicate screening and data extraction Characteristics of included studies provided Applied appropriate statistical methods for NMA Interpreted effect of heterogeneity on results No publication bias No COI declared	No explicit explanation of restriction to RCTs List of excluded studies not provided Risk of bias was high or unclear due to random sequence generation, allocation concealment, blinding of participants/personnel, blinding of assessor and selective reporting in 23.1 to 61.5% of trials Funding source of included studies not reported
Tang, 2017¹⁴
PICO elements included in research question and inclusion/exclusion criteria Search strategy provided Duplicate data extraction Characteristics of included studies provided Applied appropriate statistical methods for NMA Interpreted effect of heterogeneity on results Funding source of included studies reported (all industry funded) No COI declared No publication bias detected	No explicit explanation of restriction to RCTs List of excluded studies not provided Cochrane RoB results included but effect on results not interpreted
Tang, 2017¹⁵
PICO elements included in research question and inclusion/exclusion criteria Search strategy provided Duplicate data extraction Characteristics of included studies provided Applied appropriate statistical methods for NMA Funding source of included studies reported (all industry funded) No COI declared No publication bias detected	No explicit explanation of restriction to RCTs List of excluded studies not provided Cochrane RoB results included but effect on results not interpreted No discussion of how methodological or statistical heterogeneity impacted results
Tang, 2016 ¹¹
PICO elements included in research question and inclusion/exclusion criteria Search strategy provided Duplicate data extraction Characteristics of included studies provided Cochrane RoB results included Applied appropriate statistical methods for NMA Funding source of included studies reported (all industry funded) No COI declared No publication bias detected	No explicit explanation of restriction to RCTs List of excluded studies not provided No discussion of how methodological or statistical heterogeneity impacted results
Tang, 2016¹²
PICO elements included in research question and inclusion/exclusion criteria Duplicate data extraction Characteristics of included studies provided Cochrane RoB results included Applied appropriate statistical methods for NMA Interpreted effect of heterogeneity on results Funding source of included studies reported (all industry funded) No COI declared No publication bias detected	Search strategy not provided No explicit explanation of restriction to RCTs List of excluded studies not provided Cochrane RoB results included but effect on results not interpreted
Zaccardi, 2015¹³
PICO elements included in research question and inclusion/exclusion criteria Triplicate selection and data extraction Characteristics of included studies provided Applied appropriate statistical methods for NMA	Search strategy not provided No explicit explanation of restriction to RCTs List of excluded studies not provided RoB according to assessments using the Cochrane RoB tool was found to be high or unclear in 1.8, 10.8 and 16.7% of canagliflozin, dapagliflozin and empagliflozin RCTs, respectively, but not further addressed in interpretation of results No discussion of how methodological or statistical heterogeneity impacted results Funding source of included studies not reported Publication bias not assessed 4/6 authors received some form of funding from industry; no description of how conflicts were addressed

: COI = conflict of interest; GRADE = The Grading of Recommendations Assessment, Development and Evaluation; NMA = network meta-analysis; PICO = population, intervention, comparator, outcome; RoB = risk of bias; RCT = randomized controlled trial.

Table 7Strengths and Limitations of Guidelines using AGREE II⁹

Item	Guideline
Item	American Diabetes Association and the European Association for the Study of Diabetes, 2018²²	Diabetes Canada, 2018⁴	American College of Physicians, 2017²³	SIGN, 2017²⁴
Domain 1: Scope and Purpose
1. The overall objective(s) of the guideline is (are) specifically described.	Y	Y	Y	Y
2. The health question(s) covered by the guideline is (are) specifically described.	N	N	Y	Y
3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.	Y	Y	Y	Y
Domain 2: Stakeholder Involvement
4. The guideline development group includes individuals from all relevant professional groups.	U	Y	U	Y
5. The views and preferences of the target population (patients, public, etc.) have been sought.	N	Y	Y	Y
6. The target users of the guideline are clearly defined.	N	Y	Y	Y
Domain 3: Rigour of Development
7. Systematic methods were used to search for evidence.	Y	Y	Y	Y
8. The criteria for selecting the evidence are clearly described.	Y	Y	Y	Y
9. The strengths and limitations of the body of evidence are clearly described.	N	Y	Y	Y
10. The methods for formulating the recommendations are clearly described.	N	Y	Y	N
11. The health benefits, side effects, and risks have been considered in formulating the recommendations.	N	Y	Y	Y
12. There is an explicit link between the recommendations and the supporting evidence.	N	Y	Y	Y
13. The guideline has been externally reviewed by experts prior to its publication.	Y	Y	N	Y
14. A procedure for updating the guideline is provided.	N	N	Y	N
Domain 4: Clarity of Presentation
15. The recommendations are specific and unambiguous.	Y	Y	Y	Y
16. The different options for management of the condition or health issue are clearly presented.	Y	Y	Y	Y
17. Key recommendations are easily identifiable.	Y	Y	Y	Y
Domain 5: Applicability
18. The guideline describes facilitators and barriers to its application.	N	N	N	Y
19. The guideline provides advice and/or tools on how the recommendations can be put into practice.	Y	Y	N	Y
20. The potential resource implications of applying the recommendations have been considered.	Y	Y	Y	Y
21. The guideline presents monitoring and/or auditing criteria.	N	N	N	Y
Domain 6: Editorial Independence
22. The views of the funding body have not influenced the content of the guideline.	U	Y	Y	Y
23. Competing interests of guideline development group members have been recorded and addressed.	U	Y	Y	Y

: N = No; U = Unknown; Y = Yes.

Appendix 4. Main Study Findings and Authors’ Conclusions

Table 8Summary of Findings Included Systematic Reviews and Meta-Analyses

Main Study Findings	Authors’ Conclusion
Alfayez, 2019²⁰
No significant difference in all study outcomes (MACE, CVD mortality, nonfatal MI, nonfatal stroke, all-cause mortality, hospitalization for HF and unstable angina) between empagliflozin and canagliflozin. Ranking results Empagliflozin ranked first for reducing MACE, CV death, nonfatal MI, death from any cause and HF hospitalizations. Empagliflozin and canagliflozin ranked below placebo for stroke.	From the rank results, “… our NMA, empagliflozin was the preferred SGLT-2 inhibitor in reducing MACE, CV death, nonfatal MI, death from any cause and HF hospitalizations.” (p. 210)
Wang 2019²¹
Canagliflozin 300 mg was associated with significant reduction in weight compared to: dapagliflozin 10 mg (MD −1.26, 95% credible interval, −1.69 to −0.73), dapagliflozin 5 mg (MD −1.24, 95% credible interval −1.68 to −0.72), empagliflozin 10 mg (MD −1.03, 95% credible interval, −1.50 to −0.52), empagliflozin 25 mg (MD −0.95, 95% credible interval, −1.41 to −0.43),, ertugliflozin 5 mg (MD −0.97, 95% credible interval, −1.75 to −0.15), ipragliflozin 25 mg (MD −1.47, 95% credible interval −2.21 to −0.67), ipragliflozin 50 mg (MD −1.38, 95% credible interval −2.04 to −0.62), luseogliflozin 2.5 mg (MD −1.14, 95% credible interval, −1.64 to −0.57), and luseogliflozin 5 mg (MD −0.83, 95% credible interval, −1.37 to −0.20).. Canagliflozin 300 mg was associated with significantly more weight reduction compared to all doses of all SGLT2s included in the NMA (11 treatments). No significant differences in weight reduction between any other SGLT2s, except significant weight gain with canagliflozin 100 mg vs. 300 mg.	“…it provides a comprehensive evaluation of 7 SGLT2 inhibitors on weight reduction from baseline and the proportions of patients achieving ≥5% weight loss compared with placebo, metformin, and DDP-4 inhibitors through a network meta-analysis; moreover, it is suggested that canagliflozin 300 mg exhibited the greatest reduction on weight. It is particularly noteworthy that the effect of the 7 SGLT2 inhibitors on weight reduction from baseline was associated with dosage.” (p. 328)
Azharuddin, 2018¹⁷
No significant difference between empagliflozin, canagliflozin and dapagliflozin, for fracture risk. Rank probability analysis suggested rank order (from first to last, in terms of reduction in fracture risk) of empagliflozin, followed by dapagliflozin and canagliflozin.	“The results from the pairwise and NMA suggested that use of SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) were not significantly associated with increased risk of fracture in T2DM patients when compared to control group (placebo/active treatment).” (p. 145) “…empagliflozin… appeared to be the preferable drug followed by dapagliflozin… and canagliflozin… for the T2DM patients with risk of fracture.” (p. 186) Authors did not make concluding statements about null findings for SGLT2 network analysis specifically.
Donnan, 2018¹⁸
High dose dapagliflozin (≥10 mg) was associated with significantly increased risk of UTI compared to high dose empagliflozin (≥25 mg) (OR 1.39, 95% credible interval [1.12 to 1.72]), low dose empagliflozin (≤10 mg) (OR 1.30, 95% credible interval, 1.04-to 1.60) and low dose ertugliflozin (≤10 mg) (OR 1.43, 95% credible interval, 1.01-2.01). There were no other statistically significant differences in UTI risk across remaining SGLT2s (CANA, DAPA, EMPA, ERTU, IPRA).	“The main findings of this study suggest no dose–response association between SGLT2 inhibitors and UTI risk; however, dapagliflozin (at doses ≥ 10 mg) appears to be an exception to this general finding. Specifically, high-dose dapagliflozin compared with placebo, active comparators and empagliflozin was associated with a small increase in the risk of UTI.” (p. E600)
Zhuang, 2018¹⁹
No significant difference between canagliflozin, empagliflozin and dapagliflozin and risk of MACE or all-cause mortality.	“Our findings can be summarized as follows: first, among anti-diabetic agents included in the network, SGLT2i in class comparisons, and vildagliptin in individual comparisons, respectively ranked first in terms of MACE.” (p. 6) Authors did not make concluding statements about null findings for SGLT2 network analysis specifically.
Li, 2017¹⁶
Category effects Empagliflozin associated with significantly lower risk of UTI than dapagliflozin (OR 0.79, 95% CI, 0.64 to 0.97). No other differences between other SGLT2 treatments (IPRA, LUSEO, EMPA, DAPA and CANA) and UTI risk were observed. No significant differences in risk of genital infection between any SGLT2 treatment (IPRA, LUSEO, EMPA, DAPA, CANA). Dose effects Empagliflozin 25 mg was associated with significantly lower risk of UTI than dapagliflozin 10 mg (OR 0.75, 95% CI, 0.60 to 0.94) Dapagliflozin 10 mg was associated with significantly higher risk of UTI than dapagliflozin 2.5 mg (OR 1.65, 95% CI, 1.05 to 2.57). No other significant differences were observed between SGLT2 doses. Dapagliflozin 2.5 mg was associated with significantly higher risk of genital infection than dapagliflozin 10 mg (OR 1.55, 95% CI, 1.08 to 2.33). No other significant differences between SGLT2 dosages.	“… dapagliflozin appeared to have a dose–response relationship for risk of UTIs and genital infections. Higher doses of dapagliflozin were associated with more UTI and genital infection events than lower doses of dapagliflozin according to the ORs and SUCRA ranking.” (p. 353) “…incidence of UTIs and genital infections remained similar or even decreased for empagliflozin and canagliflozin. No significant differences were detected between lesuogliflozin or ipragliflozin and placebo or active treatments; however, conclusions should be drawn with caution because of sparse data (only one RCT was included for each drug.” (p. 352)
Tang, 2017¹⁴
No significant difference in overall cancer risk between any SGLT2 treatments (CANA, DAPA and EMPA)	“Our meta-analysis of current available evidence from RCTs indicates that SGLT2 inhibitor treatment is not associated with a significantly increased risk of overall cancer.” (p. 1868)
Tang, 2017¹⁵
Empagliflozin was associated with significantly fewer composite renal events compared to canagliflozin (OR 0.48, 95% CI, 0.29 to 0.82) and dapagliflozin (OR 0.38, 95% CI, 0.28 to 0.51). No significant difference in acute renal impairment/failure events between any SGLT2 treatments (CANA, DAPA or EMPA). Rank probability analysis The authors conducted mean rank analysis which calculates the probability of a treatment being the safest, second safest, etc. The rank order of treatments, from most safe to least safe, is presented below, by outcome: For composite renal events: rank order (most to least) of empagliflozin, followed by luseogliflozin (only 1 trial), placebo, other treatments, canagliflozin and then canagliflozin. For acute renal impairment/failure: rank order (most to least) of empagliflozin, canagliflozin, dapagliflozin, placebo, and other active treatments.	“…dapagliflozin was consistently associated with a significantly higher risk of composite renal events than was placebo. (p. 1113) “Our pairwise meta-analysis also showed that canagliflozin was significantly associated with elevated risk of composite renal events, despite a non-significantly increased risk being observed in the network meta-analysis.” (p. 1113) “…only empagliflozin was significantly associated with a lower risk of both composite renal events and acute renal impairment/failure events than placebo.” (p. 1109) “The likelihood of renal-related adverse events may depend on whether and to what extent the drug is cleared from the body through kidney excretion. It is reported that ~75% of dapagliflozin is eliminated by the renal pathway, while the other 2 SGLT2 inhibitors appear to be less subject to renal clearance (33% of canagliflozin and 54% of empagliflozin)” (p. 1113) The authors did not make concluding statements about the with-in class SGLT2 network analysis results.
Tang, 2016¹¹
No significant difference in MACE risk, all-cause mortality, HF/HF requiring hospitalization, angina/unstable angina requiring hospitalization, AF or TIA between any SGLT2 treatments. Rank probability analysis The authors conducted mean rank analysis which calculates the probability of a treatment being the safest, second safest, etc. The rank order of treatments, from most safe to least safe, is presented below, by outcome: For MACE: rank order of empagliflozin, dapagliflozin, placebo, canagliflozin and other active treatments. For all-cause mortality: rank order of empagliflozin, canagliflozin, placebo, dapagliflozin and other active treatments. For HF/HF requiring hospitalization: rank order of dapagliflozin, empagliflozin, canagliflozin, placebo, and other active treatments. For unstable angina/angina requiring hospitalization: rank order of canagliflozin, dapagliflozin, empagliflozin, placeo and other active treatments. For AF: rank order of empagliflozin, canagliflozin, dapagliflozin, placebo and other active treatments. For TIA: rank order of dapagliflozin, empagliflozin, canagliflozin, other active treatments and placebo.	“For the primary outcomes, only empagliflozin appeared associated with a lower risk of MACE and all-cause mortality compared to placebo, whereas neither dapagliflozin nor canagliflozin was significantly associated with any harm.” (p. 1778) “The protective effect of MACE and all-cause mortality from empagliflozin was largely driven by the EMPA-REG OUTCOME trial. Our findings regarding the CV benefits of empagliflozin should be interpreted cautiously” (p. 1777) The authors did not make concluding statements about the with-in class SGLT2 network analysis results.
Tang, 2016¹²
No significant difference in risk of fracture between any SGLT2 treatments (CANA, DAPA, or EMPA).	“The results from the direct and indirect evidence showed that SGLT2 inhibitors were not significantly associated with an increased risk of fracture.”(p. 1202)
Zaccardi, 2015¹³
Significantly reduced HbA1c (%) for: Canagliflozin 300 mg compared to dapagliflozin 5 mg (MD −0.30, 95% CI, −0.45 to −0.15), dapagliflozin 10 mg (MD −0.21, 95% CI, −0.33 to −0.08), empagliflozin 10 mg (MD −0.26, 95% CI, −0.39 to −0.13) and empagliflozin 25 mg (MD −0.20, 95% CI, −0.33 to −0.08) Significantly reduced FBG (mmol/L) for: canagliflozin 300 mg compared to dapagliflozin 5 mg (MD −0.81, 95% CI, −1.16 to −0.46), dapagliflozin 10 mg (MD −0.55, 95% CI, −0.86 to −0.25), empagliflozin 10 mg (MD −0.59, 95% CI, −0.90 to −0.28), and empagliflozin 25 mg (MD −0.45, 95% CI, −0.76 to −0.14). canagliflozin 100 mg compared to dapagliflozin 5 mg (MD −0.48, 95% CI, −0.83 to −0.13) Significantly increased FBG (mmol/L) for: dapagliflozin 5 mg compared to empagliflozin 25 mg (MD 0.36, 95% CI, 0.05 to 0.67) Significantly reduced body weight (kg) for: canagliflozin 300 mg compared to dapagliflozin 5 mg (MD −0.89, 95% CI, −1.43 to −0.35) Significantly increased body weight (kg) for: dapagliflozin 5 mg compared to empagliflozin 10 mg (MD 0.66, 95% CI, 0.16 to 1.16) and empagliflozin 25 mg (MD 0.55, 95% CI, 0.04 to 1.05) Significantly reduced SBP (mmHg) for: canagliflozin 300 mg compared to dapagliflozin 5 mg (MD −2.04, 95% CI, −3.64 to −0.43), dapagliflozin10 mg (MD −1.87, 95% CI, −3.13 to −0.61) and empagliflozin 10 mg (MD −1.55, 95% CI, −2.82 to −0.28) Significantly increased LDL (mmol/L) for: canagliflozin 300 mg compared to dapagliflozin 5 mg (MD 0.16, 95% CI, 0.02 to 0.29), dapagliflozin 10 mg (MD −0.13, 95% CI, 0.03 to 0.23), empagliflozin 10 mg (MD 0.17, 95% CI, 0.08 to 0.25), and empagliflozin 25 mg (MD 0.15, 95% CI, 0.06 to 0.23) Significantly reduced triglycerides (mmol/L) for: canagliflozin 300 mg compared to empagliflozin 10 mg (MD −0.19, 95% CI, −0.32 to −0.06) and empagliflozin 25 mg (MD −0.22, 95% CI −0.35 to −0.09) canagliflozin 100 mg compared to empagliflozin 10 mg (MD −0.15, 95% CI, −0.28 to −0.02) and empagliflozin 25 mg (MD −0.18, 95% CI, −0.31 to −0.05) Significantly increased risk of hypoglycemia for: canagliflozin 300 mg compared to empagliflozin 10 mg (OR 1.40, 95% CI, 1.05 to 1.86) canagliflozin 100 mg compared to dapagliflozin 10 mg (OR 1.48, 95% CI, 1.17 to 1.87) and empagliflozin 10 mg (OR 1.37, 95% CI, 1.03 to 1.82) Significantly increased risk of UTI for: dapagliflozin 10 mg compared to empagliflozin 25 mg (OR 1.39, 95% CI, 1.07 to 1.81) No significant differences in DBP, HDL, total cholesterol or risk of genital infections between SGLT2 treatments	“The highest dose of canagliflozin reduced HbA1c, FPG and systolic blood pressure to a greater extent compared with dapagliflozin and empagliflozin at any dose. Conversely, the highest doses of SGLT2 inhibitors did not differ in the extent of body weight and diastolic blood pressure reduction or HDL cholesterol increase. Whilst incomplete data on total cholesterol limited a comparative and overall assessment, differences among inhibitors were found for LDL cholesterol and triglycerides (with the highest dose of canagliflozin decreasing triglycerides versus empagliflozin at any dose and increasing LDL cholesterol versus all other SGLT2 inhibitors). Among SGLT2 inhibitors, the risk of urinary tract and genital infection was similar, while at their highest doses canagliflozin increased the risk of hypoglycemia compared with dapagliflozin, also accounting for different background therapies.” (p. 791)

: AE = adverse event; CV = cardiovascular; DBP = diastolic blood pressure; HbA1c = glycated hemoglobin; HDL = high density lipoprotein; HF = heart failure; MACE = major adverse cardiovascular events; MI = myocardial infarction; MI = myocardial infarction; OR = odds ratio; SBP = systolic blood pressure; SUCRA = surface under the cumulative ranking curve UTI = urinary tract infection.

Table 9Summary of Recommendations in Included Guidelines

Recommendations	Strength of Evidence and Recommendations
American Diabetes Association and European Association for the Study of Diabetes²²
“Among patients with ASCVD in whom HF coexists or is of special concern, SGLT2 inhibitors are recommended” (p. 2472)	None provided
“For patients with type 2 diabetes and CKD, with or without CVD, consider the use of an SGLT2 inhibitor shown to reduce CKD progression or, if contraindicated or not preferred, a GLP-1 receptor agonist shown to reduce CKD progression.” (p. 2473)	None provided
Diabetes Canada, 2018⁴
“8. In adults with type 2 diabetes without clinical CVD in whom glycemic targets are not achieved with existing antihyperglycemic medication(s), incretin agents (DPP-4 inhibitors or GLP-1 receptor agonists) and/or SGLT2 inhibitors should be considered as add-on medication over insulin secretagogues, insulin and TZDs to improve glycemic control if lower risk of hypoglycemia and/or weight gain are priorities.” (p. S99).	Grade A, Level 1A
“16. Metformin, insulin secretagogues and SGLT2 inhibitors should be temporarily withheld during acute illnesses associated with reduced oral intake or dehydration.” (p. S100)	Grade D, Consensus
“17. SGLT2 inhibitors should be temporarily withheld prior to major surgical procedures, and during acute infections and serious illness to reduce the risk of ketoacidosis.” (p. S100)	Grade D, Consensus
ACP, 2017²³
“Recommendation 2: ACP recommends that clinicians consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered. ACP recommends that clinicians and patients select among medications after discussing benefits, adverse effects, and costs.” (p. 279)	Weak recommendation; moderate-quality evidence
SIGN, 2017²⁴
“SGLT2 inhibitors should be considered as an add-on therapy to metformin in people with type 2 diabetes.” (p. 23)	Strong recommendation Strength of evidence assessed but not tied directly to each recommendation statement (range: high-quality meta-analysis, SR of RCTs or RCTs with a very low risk of bias [1++], and well-conducted meta-analyses, SRs or RCTs with low risk of bias [1+]).
“In individuals with type 2 diabetes and established cardiovascular disease, SGLT2 inhibitors with proven cardiovascular benefit (currently empagliflozin and canagliflozin) should be considered.” (p. 6)	Strong recommendation Strength of evidence assessed but not tied directly to each recommendation statement (range: high-quality meta-analysis, SR of RCTs or RCTs with a very low risk of bias [1++], and well-conducted meta-analyses, SRs or RCTs with low risk of bias [1+]).

: ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CVD = cardiovascular disease; GLP-1 = glucagon-like peptide-1; HF = heart failure; SGLT2 = sodium-glucose co-transporter 2.

Appendix 5. Overlap between Included Systematic Reviews

Table 10Primary Study Overlap between Included Systematic Reviews

First Author	Year	Alfayez 2019²⁰	Wang 2019²¹	Azharuddin 2018¹⁷	Donnan 2018¹⁸	Zhuang 2018¹⁹	Li 2017¹⁶	Tang 2017¹⁴	Tang 2017¹⁵	Tang 2016¹¹	Tang 2016¹²	Zaccardi 2016¹³
Amin	2015	▪			▪
Amin	2015				▪
Araki	2016				▪				▪
Araki	2015			▪	▪	▪	▪	▪	▪		▪	▪
Aronson	2018		▪
Bailey	2015					▪	▪	▪				▪
Bailey	2013			▪	▪	▪	▪	▪	▪	▪	▪	▪
Bailey	2012		▪		▪	▪	▪	▪	▪			▪
Barnett	2014			▪	▪	▪	▪	▪	▪	▪	▪
Bode	2015			▪	▪	▪	▪	▪	▪	▪	▪	▪
Bode	1995					▪
Bolinder	2014			▪	▪		▪	▪	▪		▪	▪
Cefalu	2015			▪	▪	▪	▪	▪	▪	▪	▪	▪
Dagogo-Jack	2017				▪
DeFronzo	2015			▪	▪		▪	▪		▪	▪	▪
Del Prato	2015				▪	▪						▪
Ferrannini	2013		▪	▪	▪	▪	▪	▪	▪	▪	▪	▪
Ferrannini	2010		▪		▪	▪
Fonseca	2013		▪		▪
Forst	2014			▪		▪	▪	▪	▪	▪	▪	▪
Frias	2016				▪		▪
Goto	2012				▪
Grunberger	2018				▪
Gupta	2017		▪		▪
Hadjadj	2016			▪	▪		▪	▪
Haering	2015				▪	▪	▪					▪
Haneda	2016						▪		▪
Haring	2014			▪			▪	▪	▪	▪	▪
Haring	2013			▪				▪	▪	▪	▪
Heerspink	2013				▪
Henry	2018				▪
Henry	2012		▪	▪	▪	▪	▪	▪	▪	▪	▪	▪
Hollander	2018				▪
Ikeda	2015		▪
Inagaki	2015			▪				▪	▪
Inagaki	2014		▪		▪		▪			▪	▪	▪
Inagaki	2013		▪						▪
Ishihara	2016				▪
Ito	2017				▪
Jabbour	2014			▪	▪	▪	▪	▪	▪	Y	▪	▪
Ji	2015				▪
Ji	2014		▪		▪		▪	▪	▪			▪
Kadokura	2014				▪
Kadowaki	2017			▪	▪
Kadowaki	2015		▪		▪		▪	▪				▪
Kadowaki	2014		▪
Kaku	2014		▪	▪	▪		▪		▪	▪	▪	▪
Kaku	2013		▪		▪
Kashiwagi	2015		▪		▪
Kashiwagi	2015				▪
Kashiwagi	2014		▪		▪
Kohan	2014			▪	▪	▪	▪	▪	▪		▪
Kovacs	2015				▪							▪
Kovacs	2014			▪			▪	▪	▪	▪	▪
Lavalle-Gonzalez	2013			▪	▪	▪	▪	▪	▪	▪	▪	▪
Leiter	2015			▪	▪	▪	▪	▪	▪	▪	▪	▪
Leiter	2014			▪	▪	▪	▪	▪	▪	▪	▪	▪
Lewin	2015		▪	▪	▪		▪	▪	▪	▪	▪	▪
List	2009		▪		▪
Ljunggren	2012					▪				▪
Lu	2016				▪		▪
MaldonadoLutomirsky	2016				▪	▪
Mathieu	2015			▪	▪		▪	▪	▪	▪	▪	▪
Mattaei	2015				▪		▪	▪	▪	▪	▪	▪
Merker	2015				▪		▪					▪
Mudaliar	2014				▪
Nauck	2014					▪
Nauck	2011			▪		▪	▪	▪	▪	▪	▪
Neal	2015	▪		▪	▪	▪			▪		▪	▪
Nishimura	2015				▪
Pratley	2018				▪
Qiu	2014				▪				▪
Ridderstrale	2014			▪	▪	▪	▪	▪	▪	▪	▪	▪
Rodbard	2016			▪	▪
Roden	2013		▪	▪		▪	▪	▪	▪	▪		▪
Roden	2015		▪		▪	▪
Rosenstock	2018				▪
Rosenstock	2016		▪		▪		▪	▪	▪	▪
Rosenstock	2015			▪	▪		▪	▪	▪	▪	▪	▪
Rosenstock	2015				▪		▪	▪	▪	▪	▪	▪
Rosenstock	2014			▪	▪	▪	▪	▪	▪	▪	▪	▪
Rosenstock	2012				▪	▪	▪	▪	▪		▪	▪
Rosenstock	2012				▪
Ross	2015				▪
Sasaki	2015				▪
Schernthaner	2013			▪		▪	▪	▪	▪	▪	▪	▪
Schumm-Draeger	2015				▪				▪
Seino	2018				▪
Seino	2014				▪
Seino	2014		▪		▪
Softeland	2017			▪	▪
Stenlof	2014		▪			▪
Stenlof	2013		▪	▪	▪	▪	▪	▪	▪	▪	▪	▪
Strojek	2014				▪		▪					▪
Strojek	2011			▪		▪		▪	▪	▪	▪
Sykes	2015				▪
Tanizawa	2014				▪
Terauchi	2017				▪
Terra	2017		▪		▪
Tikkanen	2015				▪			▪	▪
Townsend	2016				▪
Wan Seman	2016				▪
Weber	2016				▪				▪
Wilding	2014				▪	▪	▪	▪	▪			▪
Wilding	2013			▪	▪	▪	▪	▪	▪	▪	▪	▪
Wilding	2013				▪
Wilding	2012			▪		▪				▪	▪
Winding	2009				▪				▪
Yale	2014			▪	▪	▪	▪	▪	▪	▪	▪
Yale	2013					▪
Yang	2017				▪
Yang	2015						▪		▪
Yang	2014				▪
Zhao	2015				▪
Zinman	2015	▪			▪		▪		▪
Zinman	2014							▪		▪	▪
Zinman	2012					▪

About the Series

CADTH Rapid Response Report: Summary with Critical Appraisal

ISSN: 1922-8147

Version: 1.0

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

Suggested citation:

Sodium-glucose Co-transporter 2 Inhibitors for the Treatment of Type 2 Diabetes. Ottawa: CADTH; 2019Jun. (CADTH rapid response report: summary with critical appraisal).

Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.

While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.

CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.

This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.

Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third party supplier of information.

This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.

This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

Bookshelf ID: NBK545104PMID: 31433607

PubReader
Print View
Cite this Page
Amanda S, Butcher R. Sodium-glucose Co-transporter 2 Inhibitors for the Treatment of Type 2 Diabetes: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Jun 14.
PDF version of this title (1.4M)

In this Page

Context and Policy Issues
Research Questions
Key Findings
Methods
Summary of Evidence
Conclusions and Implications for Decision or Policy Making
References
Selection of Included Studies
Characteristics of Included Publications
Critical Appraisal of Included Publications
Main Study Findings and Authors’ Conclusions
Overlap between Included Systematic Reviews

Other titles in this collection

CADTH Rapid Response Reports

Related information

NLM Catalog
Related NLM Catalog Entries
PMC
PubMed Central citations
PubMed
Links to PubMed

Recent Activity

Clear Turn Off Turn On

Sodium-glucose Co-transporter 2 Inhibitors for the Treatment of Type 2 Diabetes:...
Sodium-glucose Co-transporter 2 Inhibitors for the Treatment of Type 2 Diabetes: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Bookshelf

Sodium-glucose Co-transporter 2 Inhibitors for the Treatment of Type 2 Diabetes: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines

Abbreviations

Context and Policy Issues

Research Questions

Key Findings

Methods

Literature Search Methods

Selection Criteria and Methods

Table 1

Exclusion Criteria

Critical Appraisal of Individual Studies

Summary of Evidence

Quantity of Research Available

Summary of Study Characteristics

Study Design

Table 2

Country of Origin

Patient Population

Interventions and Comparators

Outcomes

Summary of Critical Appraisal

Systematic reviews with network meta-analysis

Evidence-based guidelines

Summary of Findings

Comparative clinical effectiveness of sodium-glucose co-transporter 2 inhibitors

Table 3

HbA1c

Fasting blood glucose

Body weight

All-cause mortality and MACE

Cardiovascular death

Heart failure

SBP

LDL

Triglycerides

Non-fatal myocardial infarction

Non-fatal stroke

Unstable angina/angina requiring hospitalization

Atrial fibrillation

Transient ischemic attack

Cancer

Renal outcomes

Fracture risk

Hypoglycaemia

Urinary tract infection

Genital infection

Comparative cost-effectiveness of sodium-glucose co-transporter 2 inhibitors

Evidence-based guidelines regarding the use of sodium-glucose co-transporter 2 inhibitors

Limitations

Conclusions and Implications for Decision or Policy Making

References

Appendix 1. Selection of Included Studies

Appendix 2. Characteristics of Included Publications

Table 4Characteristics of Included Systematic Reviews and Meta-Analyses

Table 5Characteristics of Included Guidelines

Appendix 3. Critical Appraisal of Included Publications

Table 6Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR II8

Table 7Strengths and Limitations of Guidelines using AGREE II9

Appendix 4. Main Study Findings and Authors’ Conclusions

Table 8Summary of Findings Included Systematic Reviews and Meta-Analyses

Table 9Summary of Recommendations in Included Guidelines

Appendix 5. Overlap between Included Systematic Reviews

Table 10Primary Study Overlap between Included Systematic Reviews

About the Series

Suggested citation:

Views

In this Page

Other titles in this collection

Related information

Similar articles in PubMed

Recent Activity

Table 6Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR II⁸

Table 7Strengths and Limitations of Guidelines using AGREE II⁹